October 2019 Issue
Anorexia and the Gut Microbiome — Looking Beyond the Debate Over Genetics vs Environment
By Carrie Dennett, MPH, RDN, CD
Today’s Dietitian
Vol. 21, No. 10, P. 28
Anorexia nervosa (AN)—an eating disorder characterized by extreme weight loss or failure to gain expected weight accompanied by fear of weight gain—has the highest mortality rate of any psychiatric illness, and only one-half of patients experience long-term recovery.1,2 Patients with AN often experience other psychological and physiological disturbances, including anxiety, depression, and gastrointestinal (GI) distress, further complicating treatment.3-5
The Academy for Eating Disorders recently published “Nine Truths About Eating Disorders.” Truths seven and eight are “Genes and environment play important roles in the development of eating disorders,” and “Genes alone do not predict who will develop eating disorders.”6 AN research has tended to focus on environment and, to a lesser extent, genetics, but there’s an increasing, and intriguing, focus on the potential role of the gut microbiota, that collection of trillions of bacteria and other microbes in our large intestine. An imbalance in the gut microbiota is associated with a number of physical and mental health conditions; AN may be one of them.
“Multiple disease processes result in the symptom cluster we call anorexia nervosa,” says Jessica Setnick, MS, RD, CEDRD-S, Dallas-based author of The Eating Disorders Clinical Pocket Guide and owner of www.UnderstandingNutrition.com. “Some are biologically based, others are addiction related, stress or trauma related, or environmental. Anorexia of biological origin may be related to an altered microbiome; either a microbiome that is depleted or abnormal as a result of malnutrition, or as a preexisting condition that contributed to the disease process.”
The Microbiome-Gut-Brain Axis
How can the gut microbiota and microbiome influence the development or progression of AN? One pathway is through our brains. The gut-brain axis is the two-way communication between the central nervous system (CNS) and the enteric nervous system (ENS). The ENS covers the entire GI tract, so the gut-brain axis links the emotional and cognitive centers of the brain with intestinal functions.7 A more recent twist is the idea of a microbiome-gut-brain axis, based on evidence that the microbiota interacts locally with intestinal cells and the ENS, but also has direct interaction with the CNS via neural, endocrine, immune, and metabolic pathways.7-10 The microbiota has even been called the “peacekeeper” between the gut and brain.11 Research in twins suggests our genes can affect our gut microbiota and that our genome and our microbiome can interact in ways that influence our phenotype.12 Several preliminary studies have found disturbances in the gut microbiota—both reduced diversity and alterations in numbers of specific microbes—that may contribute to the AN disease process.13-17
The Center for Excellence in Eating Disorders (CEED) at University of North Carolina is researching the role of both the genome and the microbiome in eating disorders through the Anorexia Nervosa Genetics Initiative and Anorexia Nervosa: Investigation of the Gut Microbiome and Anxiety.18,19 There’s much debate about which part of the trifecta of genes, microbes, and the environment plays the most significant role in the development and progression of a number of physical and mental health conditions—including AN.
“As you can imagine, in order to address the trifecta, we need large, well-characterized samples, preferably longitudinally collected, in order to come up with robust conclusions,” says Cynthia Bulik, PhD, FAED, founding director of CEED, adding that her team currently is collecting that information. “We are laying the groundwork for this question now, but, as of yet, don’t have answers.”
Tammy Beasley, RDN, CEDRD, CSSD, vice president of clinical nutrition services at Birmingham, Alabama–based Alsana Eating Disorder Treatment & Recovery Centers, says the majority of our body’s serotonin—a neurotransmitter that contributes to well-being and happiness—is made in the gut. “This is wonderful news if you have a well-nourished and well-functioning gut,” she says. “It’s the actual vitamins and minerals found in a wide variety from all food groups that act as ‘spark plugs’ to ignite the production of the gut serotonin itself.” A gut that’s malnourished from starvation and periods of restriction, combined with a limited list of “allowed” foods, creates a perfect storm that mechanically interferes with normal serotonin production, she adds.
Interestingly, while individuals currently struggling with AN tend to have levels of serotonin that are too low for well-being, studies have found that women who have recovered from AN have excessive serotonin in the brain, which may contribute to high levels of anxiety and obsessive behavior.20-22 This is likely because they have a genetic variant that leads to increased serotonin while in a nonstarved state.23 “Which comes first?” Beasley asks. “A malnourished gut that doesn’t work well in and of itself, or [that doesn’t] have the necessary vitamins and minerals needed to make serotonin because of very limited food sources—or a preexisting overabundance of serotonin levels in the brain causing higher anxiety and obsessional thinking, which normalizes only if less food is eaten in the first place?”
The Chicken or the Egg?
A malnourished gut not only can affect mental health but also can reduce microbial diversity, which may contribute to AN through other pathways. For example, there’s substantial evidence that our gut microbes influence our metabolism and behavior. This involves weight regulation—including how much energy we extract from food and how we accumulate and store fat—energy metabolism, satiety, anxiety, and stress.24,25 Bulik and her team have hypothesized that the microbial population that develops in patients with AN may affect both behavior and metabolism, making recovery challenging,24 but do changes to the microbiota precede anorexia onset, or do they come later? Currently, that’s a question without an answer, Bulik says.
“On the most basic level, it is not possible to get samples from someone before they develop the illness, so we can’t say whether something about their microbiome predisposes them to AN or if the starvation associated with AN, or something else inherent to the illness, disrupts the microbiota,” she says.
One of the core elements of treatment for anorexia is renourishment, also known as refeeding. Many patients with anorexia experience a period of hypermetabolism during this period, which can be extremely uncomfortable, complicating recovery.24 “It is well known that some people with AN require heroic numbers of calories to restore weight—4,000 to 6,000 kcal/day—but we don’t really know why,” Bulik says, adding that while there are many theories, nothing really explains or predicts it. “For some this doesn’t happen; for others it does and for variable lengths of time.”
The drastic changes to the gut microbiota observed in AN patients could be adaptations to prolonged dietary restriction—effectively, starvation—with microbes suited to a low-energy environment more likely to survive and dominate in the competitive gut environment.5,26,27 For example, a 2016 study found that patients with AN have higher levels of bacteria that thrive on eating the intestinal mucus layer,13 which could disrupt the integrity of the intestinal barrier, increasing gut permeability and possibly accounting for the increased risk of autoimmune disorders in AN.15,28 When these microbes are disrupted by the presence of food, this may cause GI discomfort as part of the microbes’ attempt to push their host back to the status quo.5,15,26,29,30
“There is a lot of GI distress in AN—during the illness, definitely during refeeding, and even after recovery,” Bulik says. “If there is anything we can do on the microbial level to mitigate or assuage that distress in service of enhancing recovery from AN, we would be overjoyed to look at that in the future.”
Even when renourishment is “successful,” with patients regaining a healthy weight, relapses are common, and it appears they may have a low weight set point to which the body wants to revert.24
“The existing literature on the gut-brain axis evokes a model in which changes in gut microbial communities associated with extreme weight loss may perpetuate and contribute to AN via effects on weight and mood, but further research is needed to define and understand the alterations and functional effects of AN intestinal microbiotas on adiposity and behavior,” Bulik says. “This research is key to designing microbiota-modulating treatment strategies, such as promotion or elimination of specific bacterial taxa, which could improve the psychological and physical treatment experience of patients and would comprise a significant therapeutic advance in treatment of AN.”
Bulik’s team has done one study looking at whether the microbiota changes measurably during renourishment, which suggested that patients with anorexia still have lower microbial diversity at discharge, but it was too small to answer the question thoroughly.31 She says they need to look more deeply at what microbes are there and what those microbes are doing. Her team is currently collecting samples and data that should make this closer look possible.
“One of the things that I preach to people who are recovering is to be vigilant for periods of negative energy balance even well after recovery,” Bulik says. “There seems to be something about that state that can precipitate relapse—whether genes and/or the intestinal microbiota are involved is not yet known.” This is where research aiming to profile the gut microbiota may help.
Microbial Profiling and Probiotics
Profiling the gut microbiota—determining overall diversity as well as the presence or absence of specific microbes—may help determine which patients may struggle the most with weight restoration, as well as who’s more likely to relapse. Knowing which microbial species need to be introduced or nurtured, and which need to be eliminated, could make treatment less painful and stressful.25
“Weight restoration and renourishment in anorexia nervosa is hard work and is often uncomfortable due to GI symptoms and simply the amount of food that is required to restore weight,” Bulik says. “If there were some way to reduce the GI discomfort associated with refeeding through targeted pre- or probiotics—not the stuff that you buy in the drug store—that would be an enormous aid to our patients for whom the process can be really agonizing.” She points to research on manipulating the diets of sheep to reduce the number of methane-producing bacteria.32 “We could theoretically follow their blueprint and find ways to renourish individuals with AN with foods and/or supplements that can help reduce GI distress.”
Connecticut-based Beth Rosen, MS, RD, CDN, of www.goodnessgraciousliving.com, tends to recommend prebiotic foods or supplements rather than probiotics for her clients who have digestive disorders but don’t have an eating disorder, pointing out that it’s unclear whether boosting numbers of particular microbes via a probiotic supplement is helpful. “For my clients with eating disorders, including AN, who suffer with GI issues, we know that with nutrition rehabilitation, GI issues will resolve on their own in most cases, so I tend to share with them the foods that are rich in prebiotics in lieu of a supplement,” Rosen says.
Marcia Herrin, EdD, MPH, RDN, LD, FAED, New Hampshire–based founder of the Dartmouth College Eating Disorders Prevention, Education, and Treatment Program and author of Nutrition Counseling in the Treatment of Eating Disorders, says she often sees doctors recommending an over-the-counter probiotic. “There isn’t enough evidence to recommend specific ones, [but] they want to give a suffering patient something to do. Even if it doesn’t help, they hope it won’t hurt. I don’t practice that way, as I want my advice to always be based on strong evidence-based consensus on treatment approaches.” She also says she has concerns that recommending foods solely because of their perceived benefits for the gut microbiota may complicate recovery, asserting that child or adolescent patients would benefit most from simply eating more calories from foods their family currently eats rather than “special” foods, and adult patients may not like, or be able to afford, prebiotic or probiotic foods.
Beasley sees two general practices among physicians treating AN clients at the residential or day treatment levels of care. “Some encourage the use of probiotics from the first day of admission based on beliefs that a malnourished gut can benefit only from probiotic support, and others are hesitant to prescribe probiotics or any additional supplement as a standard admission protocol.” She adds that adequate nutrition from real foods may be needed to heal the malnourished gut first, providing an environment in which food-based pre- and probiotics can thrive.
Fecal Transplants for Severe AN
While the right probiotic may have therapeutic potential for some AN patients, it’s unlikely to help patients with severe, chronic AN. However, there is a glimmer of hope. CEED has FDA approval to test fecal microbiota transplantation (FMT) as a treatment for severe AN. The precedent for this involves studies showing benefits from transplanting intact, uncultured microbiotas from healthy humans to individuals with Clostridium difficile–induced colitis or patients with metabolic syndrome.25
“We’re really looking forward to this study because literature is starting to emerge that’s discussing palliative care and even assisted suicide for severe and enduring anorexia nervosa. The field is very vocal and divided on these topics,” Bulik says, adding that FMT has enough potential as an additional, and important, tool to help patients recover that it’s worth testing.33-37 Bulik’s study is still in the planning stages, which includes getting ethical approvals, but the first stage will be a small open trial and then, if it proves to be safe and promising, progressing to a larger randomized controlled trial. “So many individuals with severe and enduring AN desperately want to get better but feel exhausted and even traumatized by repeated aggressive refeeding followed by relapse. We have precious little to offer these patients currently, so it’s really in their honor that we are embarking on this path. I wake up every day disbelieving that people are still dying from this illness, and that’s what fuels our determination to try something new that has scientific justification in the work we have been doing, and one published case report from the Netherlands.”
Future Research
In a 2015 paper, Bulik says there was much skepticism about the role of the gut microbiota in AN. She stresses, however, that there was once significant doubt that the Helicobacter pylori bacterium could cause peptic ulcers; yet, that discovery allowed for a cure for these ulcers, rather than just partial symptom management.26 She says a healthy skepticism is still a good idea, and that even though her team has demonstrated that gut dysbiosis present in AN patients at admission only partially normalizes after hospital-based renourishment,13 but they aren’t sure exactly what that means.
CEED has studies underway examining larger patient cohorts longitudinally, including across the phases of their treatment. Bulik says this should provide a deeper understanding of what they’re observing. “We are also collecting a lot of samples from people with bulimia nervosa and binge eating disorder along with genomic data so that we can explore how the host genome and the microbiome act and interact,” she says.
Rosen says she has several questions she hopes this research can answer. “If specific gut microbes are responsible for the expression of a gene or genes that trigger AN, what are the specific strains of microbes that need to proliferate to prevent the genes from being expressed? Conversely, how do we prohibit the growth of specific microbes that are the catalysts for gene expression of AN—or the production of their metabolites that may play a role—from thriving or becoming too numerous?”
— Carrie Dennett, MPH, RDN, CD, is the nutrition columnist for The Seattle Times, owner of Nutrition By Carrie, and author of Healthy for Your Life: A Holistic Guide to Optimal Wellness.
References
1. Arcelus J, Mitchell AJ, Wales J, Nielsen S. Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry. 2011;68(7):724-731.
2. Zipfel S, Löwe B, Reas DL, Deter HC, Herzog W. Long-term prognosis in anorexia nervosa: lessons from a 21-year follow-up study. Lancet. 2000;355(9205):721-722.
3. Zipfel S, Giel KE, Bulik CM, Hay P, Schmidt U. Anorexia nervosa: aetiology, assessment, and treatment. Lancet Psychiatry. 2015;2(12):1099-1111.
4. Waldholtz BD, Andersen AE. Gastrointestinal symptoms in anorexia nervosa. A prospective study. Gastroenterology. 1990;98(6):1415-1419.
5. Glenny EM, Bulik-Sullivan EC, Tang Q, Bulik CM, Carroll IM. Eating disorders and the intestinal microbiota: mechanisms of energy homeostasis and behavioral influence. Curr Psychiatry Rep. 2017;19(8):51.
6. Nine truths about eating disorders. Academy for Eating Disorders website. https://www.aedweb.org/resources/publications/nine-truths
7. Carabotti M, Scirocco A, Maselli MA, Severia C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28(2):203-209.
8. Forsythe P, Kunze WA. Voices from within: gut microbes and the CNS. Cell Mol Life Sci. 2013;70(1):55-69.
9. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-712.
10. Wang Y, Kasper LH. The role of microbiome in central nervous system disorders. Brain Behav Immun. 2014;38:1-12.
11. Mu C, Yang Y, Zhu W. Gut microbiota: the brain peacekeeper. Front Microbiol. 2016;7:345.
12. Goodrich JK, Waters JL, Poole AC, et al. Human genetics shape the gut microbiome. Cell. 2014;159(4):789-799.
13. Mack I, Cuntz U, Grämer C, et al. Weight gain in anorexia nervosa does not ameliorate the faecal microbiota, branched chain fatty acid profiles, and gastrointestinal complaints. Sci Rep. 2016;6:26752.
14. Borgo F, Riva A, Benetti A, et al. Microbiota in anorexia nervosa: the triangle between bacterial species, metabolites and psychological tests. PLoS One. 2017;12(6):e0179739.
15. Herpertz-Dahlmann B, Seitz J, Baines J. Food matters: how the microbiome and gut-brain interaction might impact the development and course of anorexia nervosa. Eur Child Adolesc Psychiatry. 2017;26(9):1031-1041.
16. Morita C, Tsuji H, Hata T, et al. Gut dysbiosis in patients with anorexia nervosa. PLoS One. 2015;10(12):e0145274.
17. Mörkl S, Lackner S, Müller W, et al. Gut microbiota and body composition in anorexia nervosa inpatients in comparison to athletes, overweight, obese, and normal weight controls. Int J Eat Disord. 2017;50(12):1421-1431.
18. Watson HJ, Yilmaz Z, Thornton LM, et al. Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa. Nat Genet. 2019;51(8):1207-1214.
19. Thornton LM, Munn-Chernoff MA, Baker JH, et al. The Anorexia Nervosa Genetics Initiative (ANGI): overview and methods. Contemp Clin Trials. 2018;74:61-69.
20. Bailer UF, Frank GK, Henry SE, et al. Exaggerated 5-HT1A but normal 5-HT2A receptor activity in individuals ill with anorexia nervosa. Biol Psychiatry. 2007;61(9):1090-1099.
21. Frank GK, Kaye WH, Meltzer CC, et al. Reduced 5-HT2A receptor binding after recovery from anorexia nervosa. Biol Psychiatry. 2002;52(9):895-906.
22. Kaye WH, Bailer UF, Frank GK, Wagner A, Henry SE. Brain imaging of serotonin after recovery from anorexia and bulimia nervosa. Physiol Behav. 2005;86(1-2):15-17.
23. Gorwood P, Adès J, Bellodi L, et al. The 5-HT(2A) -1438G/A polymorphism in anorexia nervosa: a combined analysis of 316 trios from six European centres. Mol Psychiatry. 2002;7(1):90-94.
24. Bulik CM, Flatt R, Abbaspour A, Carroll I. Reconceptualizing anorexia nervosa. Psychiatry Clin Neurosci. 2019;73(9):518-525.
25. Carr J, Kleinman SC, Bulik CM, Bulik-Sullivan EC, Carroll IM. Can attention to the intestinal microbiota improve understanding and treatment of anorexia nervosa? Expert Rev Gastroenterol Hepatol. 2016;10(5):565-569.
26. Bulik CM. Towards a science of eating disorders: replacing myths with realities: the fourth Birgit Olsson lecture. Nord J Psychiatry. 2016;70(3):224-230.
27. Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. PLoS One. 2009;4(9):e7125.
28. Karakuła-Juchnowicz H, Pankowicz H, Juchnowicz D, Valverde Piedra JL, Małecka-Massalska T. Intestinal microbiota — a key to understanding the pathophysiology of anorexia nervosa? Psychiatr Pol. 2017;51(5):859-870.
29. Seitz J, Belheouane M, Schulz N, Dempfle A, Baines JF, Herpertz-Dahlmann B. The impact of starvation on the microbiome and gut-brain interaction in anorexia nervosa. Front Endocrinol (Lausanne). 2019;10:41.
30. Sato Y, Fukudo S. Gastrointestinal symptoms and disorders in patients with eating disorders. Clin J Gastroenterol. 2015;8(5):255-263.
31. Kleiman SC, Watson HJ, Bulik-Sullivan EC, et al. The intestinal microbiota in acute anorexia nervosa and during renourishment: relationship to depression, anxiety, and eating disorder psychopathology. Psychosom Med. 2015;77(9):969-981.
32. Greening C, Geier R, Wang C, et al. Diverse hydrogen production and consumption pathways influence methane production in ruminants [published online June 26, 2019]. ISME J. doi: 10.1038/s41396-019-0464-2.
33. Lopez A, Yager J, Feinstein RE. Medical futility and psychiatry: palliative care and hospice care as a last resort in the treatment of refractory anorexia nervosa. Int J Eat Disord. 2010;43(4):372-377.
34. Scolan V, Praline O, Carlin N, Noël V. Ethical dilemma of the therapeutic decisions in the care of the severe chronic anorexia nervosa: about a case. Linacre Q. 2013;80(4):388-392.
35. Westmoreland P, Mehler PS. Caring for patients with severe and enduring eating disorders (SEED): certification, harm reduction, palliative care, and the question of futility. J Psychiatr Pract. 2016;22(4):313-320.
36. Yager J. The futility of arguing about medical futility in anorexia nervosa: the question is how you would handle highly specific circumstances? Am J Bioeth. 2015;15(7):47-50.
37. de Clercq NC, Frissen MN, Davids M, Groen AK, Nieuwdorp M. Weight gain after fecal microbiota transplantation in a patient with recurrent underweight following clinical recovery from anorexia nervosa. Psychother Psychosom. 2019;88(1):58-60.